4-苯胺喹唑啉类化合物合成研究进展

4-苯胺喹唑啉类化合物是一类具有广泛药理活性的喹唑啉类生物碱,在酪氨酸激酶受体(EGFR)抑制剂的研发中具有重要的作用。已经上市的此类药物有吉非替尼(gefitinib)和厄洛替尼(erlotinib)等。此类化合物的合成都是经过喹唑啉酮中间体或直接环合成4-苯胺喹唑啉。苯甲醛及其衍生物被用作反应原料,两种合成路线都要经历对苯甲醛的硝化及硝基的还原两步反应。笔者经查阅资料,设计并验证了以苯胺为原料、经靛红中间体得到4-苯胺喹唑啉类化合物的新的合成路线。本文依据这两种合成策略综述了4-苯胺喹唑啉类化合物的合成方法,并对各种方法的优缺点进行了总结,为进一步研究4-苯胺喹唑啉合成及设计具有药理活性的新化合物提供参考。

Progress on the Synthesis of 4-anilinoquinazolines

4-anilinoquinazolines are a kind of quinazoline alkaloids with excellent and extensive pharmacological activities. It plays an important role in exploring new EGFR inhibitors. There are lots of 4-anilinoquinazoline derivatives were designed and synthesized as EGFR inhibitors. And gefitinib and erlotinib were two 4-anilinoquinazolines using as anticancer drugs for the notable EGFR inhibitor activity. There are many reports about the synthesis of 4-anilinoquinazoline derivatives. And these synthesis works were summarized to two main strategies, using quinazolone as key intermediate or forming 4-anilinoquinazoline ring directly. Benzaldehyde and its derivatives were usually selected as starting materials and nitro reaction and its reduction were enrolled in the two strategies. To avoid these two steps in synthesis work, we have designed and proved a novel strategy with only five steps in our previous work. Aniline and its derivatives were used as starting materials and isatin and its derivatives were synthesized as key intermediates. Comparing with the reported strategies, our novel route was more convenient and effective for its facility post purification process and high total yields. In this work, almost all the works of synthesis of 4-anilinoquinazolines were reviewed and the advantaged and disadvantaged of each synthetic work were also elucidated. It was helpful to study the synthesis of 4-anilinoquinaolines and to seek new active compounds.